Effect of long-term and high-dose antithrombin supplementation on coagulation and fibrinolysis in patients with severe sepsis*

OBJECTIVE: Sepsis is frequently associated with coagulatory activation, which may contribute to deteriorated organ function. Antithrombin is one important endogenous coagulation inhibitor that is therapeutically applied during sepsis. This study investigates the effect of 14-day antithrombin application on coagulatory variables. DESIGN: Prospective study. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Forty patients with severe sepsis. INTERVENTIONS: Patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 20, controls) or antithrombin substitution that aimed at a plasma antithrombin activity > or =120% during a long-term (14-day) study period (n = 20, antithrombin). To allow comparative analysis of laboratory variables over time, all patients who did not survive the 14-day-period (five controls and six antithrombin patients) were prospectively excluded from the final evaluation. Their data were included in an intent-to-treat analysis. MEASUREMENTS AND MAIN RESULTS: Antithrombin supplementation normalized global coagulation tests and increased prothrombin activity as well as fibrinogen concentration, reflecting less coagulation factor consumption (percent change from baseline in prothrombin activity, p <.01 vs. controls at days 9, 11-14 of antithrombin vs. controls [unpaired Student's t-test]; fibrinogen concentration, p <.01 vs. controls at days 10, 11, 13, and 14 of antithrombin). Simultaneously, antithrombin reduced contact system activation as indicated by increasing prekallikrein activities over time (% change, p <.01 vs. controls at days 6, 9-14) and increased protein C activities when compared with controls (% change, p <.01 vs. controls at days 10-14). Most changes occurred from day 7 to day 14 of antithrombin supplementation. Antithrombin did not influence C1 esterase inhibitor, plasminogen, alpha2 antiplasmin, or platelet counts (p >.01). CONCLUSION: In this first study on long-term antithrombin therapy, antithrombin significantly reduced septic coagulatory response in patients with severe sepsis when given over 14 days.